Genetic determinants of direct oral anticoagulant (DOAC) response: evidence, limitations and barriers to clinical implementation

INTRODUCTION: Direct oral anticoagulants (DOACs) offer predictable pharmacokinetics and simplified dosing compared with warfarin, yet clinically important inter-individual variability in drug exposure, efficacy and safety persists. Pharmacogenomics can help explain this variability and advance precision anticoagulation. AREAS COVERED: This narrative review synthesizes evidence on genetic determinants of the pharmacokinetics and clinical outcomes of dabigatran, rivaroxaban, apixaban and edoxaban, identified by searching PubMed, Embase and Web of Science from inception to May 2026. Evidence from candidate-gene studies, genome-wide association studies, systematic reviews and meta-analyses was synthesized and the magnitude of reported genetic effects were compared the non-genetic determinants of exposure. Variants in CYP3A4, CYP3A5, CES1, ABCB1 and ABCG2 have been investigated for their potential effects on DOAC disposition and response. CES1 variants, particularly rs2244613, rs8192935 and rs71647871, may influence dabigatran exposure, while transporter variants may affect absorption and elimination. CYP3A4/5 and ABCG2 variation has also been associated with altered rivaroxaban and apixaban pharmacokinetics. Evidence for edoxaban, including SLCO1B1 variation, remains limited. EXPERT OPINION: Pharmacogenomics represents a promising component of individualized DOAC therapy, but routine clinical implementation is in progress. Prospective genotype-guided studies, validated polygenic and clinical-genetic scores, therapeutic concentration thresholds and diverse multiethnic validation are needed before pharmacogenomic testing can reliably inform DOAC selection and dosing.